Toxicokinetics studies sample analysis

In this regard, our laboratory demonstrated a method for the quantification of STI571 and its main metabolite, CGP 74588, in human plasma using a semi-automated PPT method and a relatively rapid LC/APCI/MS/MS analysis. The assay exhibited an excellent linearity from 4.00 to 10,000 ng/mL in human plasma. The method was utilized for the analysis of thousands of clinical samples. Furthermore, the method was routinely amenable to analysis of STI571 and CGP 74588 in cerebrospinal fluids (CSF), gastrointestinal stromal tumor (GIST) biopsy specimens, and toxicokinetic studies (data not shown). 

Another point to be made is connected with activities associated to the main study performance. The termination of the toxicokinetic part of a chronic toxicity or carcinogenicity study will obviously be delayed with respect to the experimental end of the in-life phase of the main study, if blood samples from the last treatment day are to be analysed. Should the study plan assign the end of the analytical determinations as the experimental end date, or should stiU the necropsy determine this date In analogy to the field studies, where analysis of the samples will constitute, scientifically speaking, the main... 

A. P. Bereford, Advantages of achiral HPLC as a preparative step to chiral analysis in biological samples and its use in toxicokinetic studies, Xenobiotica, 22(No7)( 1992)789. 

Sampling Interval To be able to perform valid toxicokinetic analysis, it is not only necessary to properly collect samples of appropriate biological fluids, but also to collect a sufficient number of samples at the current intervals. Both of these variables are determined by the nature of the answers sought. Useful parameters in toxico-kinetic studies are Cmax, which is the peak plasma test compound concentration Tmax, which is the time at which the peak plasma test compound concentration occurs, Cmin, which is the plasma test compound concentration immediately before the next dose is administered AUC, which is the area under the plasma test compound concentration-time curve during a dosage interval, and t which is the half-life for the decline of test compound concentrations in plasma. The samples required to obtain these parameters are shown in Table 18.12. Cmin requires one blood sample immediately before a dose is given and provides information on accumulation. If there is no accumulation in plasma, the test compound may not be detected in this sample. 

Despite the everincreasing number of applications associated with pharmaceutical bioanalysis, strong emphasis continues to be placed on the analysis of plasma samples from live-phase studies. The reason for this demand is that the concentration of a drug in plasma is the well-accepted surrogate marker for drug exposure and is essential to the study of pharmacokinetics (PK) and toxicokinetics (TK). 

Given the foregoing discussion of some of the unique characteristics of macromolecules that lead to clear differences in their pharmacokinetics compared to those typical of small-molecule drugs, there is a subset of the entire group of bioanalytical assay validation parameters that are of key importance in support of pharmacokinetics of candidate macromolecular therapeutics. Assuming demonstration of accuracy and precision of sufficient quality for the intended application of the assay (e.g., non-GLP discovery support or GLP toxicokinetic support, as discussed above), the most important characteristics of a given assay in support of pharmacokinetic studies are likely to be selectivity, specificity, and reproducibility for analysis of incurred samples. These are all related to the ability of the LBA to detect and quantitate solely, or as closely as possible to solely, the analyte of interest. 

MoniUtring anti-ChEs or their metabolites in urine and blood can be employed in two ways. The first is to give an accurate estimate of potential risk and requires a determination of the sy.stemic dose received by the worker that can be equated to doses used in laboratory studies. This requires knowledge of the metabolism and toxicokinetics of the material and obtaining specific timed samples of blood and urine for analysis and accurate calculation of absorbed doses of the parent material. Second, for screening workers for exposure to an anti-ChE, there is a need to measure metabolite to qualitatively determine that there has or has not been exposure to the anti-ChE, or else to quantitatively measure the concentration of metabolite to ensure that it has not exceeded a specific level known to be associated with the development of pcsiieide-induced adverse health effect.s. 

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